Racemic and non-racemic 4-(hydroxymethyl)pyrrolidin-3-ols have been prepared and found to have an inhibitory effect on certain enzymes and on glial GABA uptake. These pyrrolidines have also been used as building blocks for the synthesis of some compounds having antibacterial activity and also for some nucleosides analogues. Recently, (3R,4R)-4-(hydroxymethyl)-pyrrolidin-3-ol was used for the synthesis of a highly potent purine nucleoside phosphorylase (PNP) inhibitor.
The first synthesis of 3-hydroxy-4-hydroxymethylpyrrolidine was reported starting from N-benzylglycinate and ethyl acrylate and was obtained as a mixture of cis/trans isomers. The trans-racemic compound was prepared starting from fumaric acid methyl ester.
The first synthesis of the pure enantiomer (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol was reported from glucose and xylose (Schemes 1 and 2) in very low yields requiring several steps and is not practical for synthesis on a kilogram scale.
Karlsson and Hogberg reported the preparation of this compound via asymmetric 1, 3-dipolar cycloaddition using camphor sultam as a chiral auxiliary. In this synthesis, the chiral ylide used was generated from phenethylamine and the intermediates obtained were oils requiring flash chromatography for the separation of isomers.
These reported methods are considered unsuitable for various reasons. To produce kilogram quantities of these products, a practical synthesis was needed using a suitable procedure.